Phosphorus-doped fiber for flat octave spanning supercontinuum generation.

In a fiber supercontinuum (SC) source, the Raman scattering effect plays a significant role in extending the spectrum into a longer wavelength. Here, by using a phosphorus-doped fiber with a broad Raman gain spectrum as the nonlinear medium, we demonstrate flat SC generation spanning from 850 to 2150 nm. Within the wavelength range of 1.1-2.0 µm, the spectral power density fluctuation is less than 7 dB. Compared to a similar SC source based on a germanium-doped fiber with narrower Raman gain spectrum, the wavelength span is 300 nm broader, and the spectral power density fluctuation is 5 dB lower. This work demonstrates the phosphorus-doped fiber's great advantage in spectrally flat SC generation, which is of great significance in many applications such as optical coherence tomography, absorption spectroscopy, and telecommunication.

Influence of wavelength, linewidth, and temperature on second harmonic generation of a superfluorescent fiber source.

Low-coherence tunable visible light sources have a wide range of applications in imaging, spectroscopy, medicine, and so on. Second harmonic generation (SHG) based on a superfluorescent fiber source (SFS) can produce high-brightness visible light while retaining most of the characteristics of superfluorescent sources, such as low coherence, low intensity noise and flexible tunability. However, due to the limitations in phase matching conditions, SHG based on SFS is difficult to reach an equilibrium between high efficiency and robustness of phase matching to temperature variation. In this paper, based on a spectral tunable SFS, we provide a comprehensive analysis, both experimental and theoretical, of the impact of wavelength, linewidth, and temperature on the output performance of SHG. Our findings indicate that broader linewidths adversely affect conversion efficiency, yet they enhance the capacity to withstand temperature variations and central wavelength detuning, which is an advantage that traditional SHG methods do not possess. This work may pave the way for utilizing low-coherence visible light in domains and extreme environments where robust output stability becomes imperative.

Improvement of proportion of days covered for denosumab under implementation of clinical pharmacist adherence management system: normal and COVID-19 period.

We established a clinical pharmacist adherence management system (CPAMS) led by clinical pharmacists to examine whether denosumab adherence could be improved. The results showed that CPAMS could effectively improve adherence to denosumab and the treatment of osteoporosis. However, this effect weakened during the spread of infectious diseases such as COVID-19. PURPOSE: Denosumab is currently one of the drugs that can effectively reduce the risk of clinical fracture. However, as a drug requiring long-term subcutaneous injection, patient adherence to denosumab is the most important factor affecting its therapeutic efficacy. Therefore, we established a clinical pharmacist adherence management system (CPAMS) led by clinical pharmacists and examined whether denosumab adherence could be improved. METHODS: Data were collected from patients receiving denosumab in our hospital between March 2021 and May 2022. The patients who participated in the CPAMS were in the intervention group, and the rest were in the control group. We analysed the proportion of days covered (PDC) value of denosumab, distribution of subsequent visits, and proportion of patients who continued participating during the normal and coronavirus (COVID-19) periods. RESULTS: Eighty-five patients were enrolled in this retrospective study: 32 in the intervention group and 53 in the control group. The PDC values were significantly higher in the intervention group (0.9875, 0.9025-1) than in the control group (0.5, 0.5-0.5) after 1 year. The subsequent visit rate in the intervention group was 93.80%. However, none of the patients in the control group returned. In the intervention group, the ratio of timely to delayed subsequent visits was 11:19. After the COVID-19 pandemic, the PDC value of the intervention group (0.957, 0.5-1) was lower than that before COVID-19, and the ratio of timely to delayed subsequent visits was 9:13. CONCLUSIONS: Clinical pharmacist-led CPAMS could effectively improve adherence to denosumab and the treatment of osteoporosis.

Effects of iguratimod in the treatment of palindromic rheumatism: Case report.

OBJECTIVE: Palindromic rheumatism (PR) is characterized by interstitial inflammation, redness, and pain in joints and periarticular tissues. However, the pathogenesis and treatment of PR remain unknown. Herein, we report on the first use of iguratimod (IGU) - a novel small-molecule compound with anti-inflammatory effects - in the treatment of refractory PR. CASE: A male patient aged 70 years was diagnosed with PR based on medical history, clinical manifestations, and ultrasound findings. The patient was treated with IGU (25 mg PO q.d.). The disease activity was measured by the frequency of PR flares and clinical symptoms. The patient's laboratory tests were monitored for safety reasons. RESULTS: The use of IGU significantly improved pain symptoms and reduced flare frequency. After 28 days of treatment, abnormal levels of glutamic-pyruvic transaminase were observed. One month after discontinuation of IGU, flares occurred in the patient's second toe of both feet. CONCLUSION: IGU provides a new treatment option for patients with refractory PR who cannot use hydroxychloroquine. The effective treatment with IGU suggests the potential pathogenesis of PR and provides a basis for physicians to choose a new drug for PR treatment.

Iguratimod efficacy in palindromic rheumatism treatment.

BACKGROUND: As a new immunomodulator for rheumatoid arthritis, iguratimod (IGU) also has therapeutic potential in other immune diseases. In this study, we determined the effects of IGU on disease control in patients with palindromic rheumatism (PR). METHODS: Patients with PR were divided into Control group (Ctrl group) and an IGU treatment (IGU group) groups. Drug efficacy was evaluated according to the frequency of PR attacks (monthly), the visual analog scale (VAS) score of patient pain, and clinical symptoms. RESULTS: The drug positivity and disease control rates of the IGU group (100.00% and 90.91%, respectively) were significantly higher than those of the Ctrl group (61.11% and 5.56%; p = .002 and p < .001, respectively). The median number of PR flares and the VAS score of patients in the Ctrl group decreased from 3.00 (1.00-15.00) to 0.83 (0.00-12.00) and from 5 (4-6) to 4 (1-6), respectively. In the IGU group, the median number of PR attacks decreased from 4.50 (2.00-15.00) to 0.00 (0.00-0.33), and the VAS score decreased from 5 (4-6) to 0 (0-2). The IGU group exhibited a significant reduction in PR flare frequency and improvement in the VAS value (p < .001 and p < .001, respectively). CONCLUSION: Our study is the first to describe the efficacy of IGU in PR treatment. IGU can significantly reduce the number of PR flares and improve the clinical symptoms of patients with PR.

Clinical and epidemiological characteristics of 369 patients with pelvic fractures in Eastern Zhejiang Province of China: a retrospective study.

BACKGROUND: Data on the epidemiological characteristics and prognostic factors of patients with pelvic fractures are lacking, particularly in China. This study aimed to summarise the clinical and epidemiological characteristics of patients with pelvic fractures in eastern Zhejiang Province, China, and to identify risk factors for poor prognosis. METHODS: The clinical data of 369 patients with pelvic fractures admitted to the Ningbo No. 6 Hospital between September 2020 and September 2021 were retrospectively analysed. Data on the demographic characteristics; fracture classification; injury time, cause, and site; treatment plan; and prognosis were collected using the Picture Archiving and Communication System and the Hospital Information System. Differences in constituent proportions were analysed using the chi-square test. Logistic regression analysis was used to identify factors affecting patient prognosis. Statistical significance was set at p ≤ 0.05. RESULTS: Among the 369 patients, there were 206 men and 163 women, at a ratio of 1.26:1, and the average age was 53.64 ± 0.78 years. More than 50% of patients were aged 41-65 years. The average length of hospital stay was 18.88 ± 1.78 days. The three most common causes of pelvic fractures were traffic accidents (51.2%), falls from height (31.44%), and flat-ground falls (14.09%). There were significant differences in the distribution of the three causes of injury depending on age (p < 0.001), sex (p < 0.001), and occupation (p < 0.0001). Most patients were manual workers (48.8%). Furthermore, most patients (n = 262, 71.0%) underwent surgical treatment for pelvic fractures. Postoperative complications occurred in 26 patients (7.05%), and infection was the main complication (73.08%). Age (p = 0.013), occupation (p = 0.034), cause of injury (p = 0.022), treatment options (p = 0.001), and complications (p < 0.0001) were independent factors affecting the prognosis of patients with pelvic fractures. One death (0.027%) occurred, which was due to severe blood loss. CONCLUSIONS: Age, occupation, cause of injury, treatment options and complications were factors affecting patient prognosis. In addition, changes in blood flow and prevention of infection warrant attention.

Properties of Alkali-Activated Slag Cement Activated by Weakly Alkaline Activator.

Sodium sulfate (Na2SO4) and sodium carbonate (Na2CO3) are weakly alkaline activators. Alkali-activated slag (AAS) cement prepared with them shows the special advantages of long setting time and low shrinkage, but it shows slow development of mechanical properties. In the paper, Na2SO4 and Na2CO3 were used as activators and compounded with reactive magnesium oxide (MgO) and calcium hydroxide (Ca(OH)2) to optimize the setting time and mechanical properties. The hydration products and microscopic morphology were also studied using XRD, SEM, and EDS. Furthermore, the production cost and environmental benefits were compared and analyzed. The results show that Ca(OH)2 is the main influencing factor for setting time. It reacts preferentially with Na2CO3 to form CaCO3, which makes AAS paste lose plasticity rapidly and shortens the setting time, and then produces strength. Na2SO4 and Na2CO3 are the main influencing factors for flexural and compressive strength, respectively. Suitably high content is beneficial to promote the development of mechanical strength. The interaction of Na2CO3 and Ca(OH)2 shows a great effect on the initial setting time. High content of reactive MgO can shorten the setting time and increase the mechanical strength at 28 days. There are more crystal phases in hydration products. Considering the setting time and mechanical properties, the composition of activators are: 7% Na2SO4, 4% Na2CO3, 3-5% Ca(OH)2, and 2-4% reactive MgO. Compared with ordinary Portland cement (OPC) and AAS cement activated by sodium hydroxide (NaOH, NH) and water glass (WG) with the same alkali equivalent, the production cost and energy consumption are greatly reduced. Compared with P·O 42.5 of OPC, CO2 emission is reduced by 78.1%. AAS cement activated by weakly alkaline activators shows excellent environmental and economic benefits and good mechanical properties.

Effects of monthly evaluations on the rates of irrational antimicrobial prescription in the outpatient and emergency departments at Ningbo No. 6 Hospital, Ningbo, China.

BACKGROUND: Antibiotic resistance is a major global public health problem. The primary cause of antibiotic resistance is inappropriate antibiotic use. In this study, we aimed to verify whether the monthly evaluation of antibiotic prescription improves clinical antibiotic use in outpatient and emergency departments. METHODS: A minimum of 25% of the prescriptions for antibacterial drugs were randomly selected at the outpatient and emergency departments to enter the monthly evaluation system from July 2016 to June 2019. We analysed the rate of irrational prescription of antibiotics, proportion of the use of antibiotics, and consistency between the evaluation and expert groups after implementing the monthly assessment to validate the role of monthly evaluations. RESULTS: After 3 years of monthly evaluations of antibiotic prescriptions, the utilisation rate of single antibiotics in the outpatient and emergency departments was found to increase each year. Each year, a decreasing trend was observed for the irrational use of antibiotics, whereas the proportion of antibiotics to the total drugs prescribed gradually decreased in the same period. In addition, the consistency of prescription evaluation results between the evaluation and expert groups increased continuously. CONCLUSIONS: Monthly evaluation of antibiotic prescriptions is an effective management tool for the rational use of antibiotics in clinical practice. This practice could help reduce the combinative use of antibiotics, rate of irrational antibiotic prescription, and antibiotic use ratio, and play an important role in safe clinical drug use.

FGF21 promotes ischaemic angiogenesis and endothelial progenitor cells function under diabetic conditions in an AMPK/NAD+-dependent manner.

Diabetic vascular complications are closely associated with long-term vascular dysfunction and poor neovascularization. Endothelial progenitor cells (EPCs) play pivotal roles in maintaining vascular homeostasis and triggering angiogenesis, and EPC dysfunction contributes to defective angiogenesis and resultant diabetic vascular complications. Fibroblast growth factor 21 (FGF21) has received substantial attention as a potential therapeutic agent for diabetes via regulating glucose and lipid metabolism. However, the effects of FGF21 on diabetic vascular complications remain unclear. In the present study, the in vivo results showed that FGF21 efficiently improved blood perfusion and ischaemic angiogenesis in both type 1 and type 2 diabetic mice, and these effects were accompanied by enhanced EPC mobilization and infiltration into ischaemic muscle tissues and increases in plasma stromal cell-derived factor-1 concentration. The in vitro results revealed that FGF21 directly prevented EPC damage induced by high glucose, and the mechanistic studies demonstrated that nicotinamide adenine dinucleotide (NAD+ ) was dramatically decreased in EPCs challenged with high glucose, whereas FGF21 treatment significantly increased NAD+ content in an AMPK-dependent manner, resulting in improved angiogenic capability of EPCs. These results indicate that FGF21 promotes ischaemic angiogenesis and the angiogenic ability of EPCs under diabetic conditions by activating the AMPK/NAD+ pathway.

Benchmarking the mechanisms of frequent hitters: limitation of PAINS alerts.

In 2010, the pan-assay interference compounds (PAINS) rule was proposed to identify false-positive compounds, especially frequent hitters (FHs), in biological screening campaigns, and has rapidly become an essential component in drug design. However, the specific mechanisms remain unknown, and the result validation and follow-up processing schemes are still unclear. In this review, a large benchmark collection of >600,000 compounds sourced from databases and the literature, including six common false-positive mechanisms, was used to evaluate the detection ability of PAINS. In addition, 400 million purchasable molecules from the ZINC database were also applied to PAINS screening. The results indicate that the PAINS rule is not suitable for the screening of all types of false-positive results and needs more improvement.

KRT8 and KRT19, associated with EMT, are hypomethylated and overexpressed in lung adenocarcinoma and link to unfavorable prognosis.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer. To date, the prognosis of patients with LUAD remains dismal. METHODS: Three datasets were downloaded from the GEO database. Differentially expressed genes (DEGs) were obtained. FunRich was used to perform pathway enrichment analysis. Protein-protein interaction (PPI) networks were established and hub genes were obtained by Cytoscape software. GEPIA was utilized to conduct correlation and survival analysis. Upstream miRNAs of DEGs were predicted via miRNet database, and methylation status of promoters of DEGs was determined through UALCAN database. RESULTS: A total of 375 DEGs, including 105 and 270 up-regulated and down-regulated genes in LUAD, were commonly appeared in three datasets. These DEGs were significantly enriched in mesenchymal-to-epithelial transition (MET) and epithelial-to-mesenchymal transition (EMT). About 8 up-regulated and 5 down-regulated DEGs were commonly appeared in EMT/MET-related gene set and the top 50 hub gene set. Among the 13 genes, increased expression of KRT8 and KRT19 indicated unfavorable prognosis whereas high expression of DCN and CXCL12 suggested favorable prognosis in LUAD. Correlation analysis showed that KRT8 (DCN) expression was linked to KRT19 (CXCL12) expression. Further analysis displayed that KRT8 and KRT19 could jointly forecast poor prognosis in LUAD. About 42 and 2 potential miRNAs were predicted to target KRT8 and KRT19, respectively. Moreover, methylation level analysis demonstrated that KRT8 and KRT19 were significantly hypomethylated in LUAD compared with normal controls. CONCLUSIONS: All these findings suggest that KRT8 and KRT19 are hypomethylated and overexpressed in LUAD and associated with unfavorable prognosis.

Endothelial Overexpression of Metallothionein Prevents Diabetes-Induced Impairment in Ischemia Angiogenesis Through Preservation of HIF-1α/SDF-1/VEGF Signaling in Endothelial Progenitor Cells.

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet- and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in db/db mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from patients with diabetes exhibited decreased MT expression, increased cell apoptosis, and impaired tube formation, while cultured JTMT EPCs had enhanced cell survival, migration, and tube formation in hypoxic/hyperglycemic conditions compared with WT EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT's pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

Interleukin-1ß augments the angiogenesis of endothelial progenitor cells in an NF-κB/CXCR7-dependent manner.

Endothelial progenitor cells (EPCs) are able to trigger angiogenesis, and pro-inflammatory cytokines have beneficial effects on angiogenesis under physiological and pathological conditions. C-X-C chemokine receptor type 7 (CXCR-7), receptor for stromal cell-derived factor-1, plays a critical role in enhancing EPC angiogenic function. Here, we examined whether CXCR7 mediates the pro-angiogenic effects of the inflammatory cytokine interleukin-1ß (IL-1ß) in EPCs. EPCs were isolated by density gradient centrifugation and angiogenic capability was evaluated in vitro by Matrigel capillary formation assay and fibrin gel bead assay. IL-1ß elevated CXCR7 expression at both the transcriptional and translational levels in a dose- and time-dependent manner, and blockade of the nuclear translocation of NF-κB dramatically attenuated the IL-1ß-mediated up-regulation of CXCR7 expression. IL-1ß stimulation significantly promoted EPCs tube formation and this effect was largely impaired by CXCR7-siRNA transfection. IL-1ß treatment stimulated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation, and inhibition of Erk1/2 phosphorylation partially impaired IL-1ß-induced tube formation of EPCs but without significant effects on CXCR7 expression. Moreover, blocking NF-κB had no significant effects on IL-1ß-stimulated Erk1/2 phosphorylation. These findings indicate that CXCR7 plays an important role in the IL-1ß-enhanced angiogenic capability of EPCs and antagonizing CXCR7 is a potential strategy for inhibiting angiogenesis under inflammatory conditions.

Application of Negative Design To Design a More Desirable Virtual Screening Library.

Negative design is a group of virtual screening methods that aims at weeding out compounds with undesired properties during the early stages of drug development. These methods are mainly designed to predict three important types of pharmacological properties: drug-likeness, frequent hitters, and toxicity. In order to achieve high screening efficiency, most negative design methods are physicochemical property-based and/or substructure-based rules or filters. Such methods have advantages of simplicity and good interpretability, but they also suffer from some defects such as inflexibility, discontinuity, and hard decision-making. In this review, the advances in negative design for the evaluations of drug-likeness, frequent hitters, and toxicity are outlined. In addition, the related Web servers and software packages developed recently for negative design are summarized. Finally, future research directions in this field are discussed.

Frequent hitters: nuisance artifacts in high-throughput screening.

One of the major challenges in early drug discovery is the recognition of frequent hitters (FHs), that is, compounds that nonspecifically bind to a range of macromolecular targets or false positives caused by various types of assay interferences. In this review, we survey the mechanisms underlying different types of FHs, including aggregators, spectroscopic interference compounds (i.e., luciferase inhibitors and fluorescent compounds), chemical reactive compounds, and promiscuous compounds. We also review commonly used experimental detection techniques and computational prediction models for FH identification. In addition, the rational applications of these computational filters are discussed. It is believed that, with the rational use of FH filters, the efficiency of drug discovery will be significantly improved.

Modulating Enzyme Activity by Altering Protein Dynamics with Solvent.

Optimal enzyme activity depends on a number of factors, including structure and dynamics. The role of enzyme structure is well recognized; however, the linkage between protein dynamics and enzyme activity has given rise to a contentious debate. We have developed an approach that uses an aqueous mixture of organic solvent to control the functionally relevant enzyme dynamics (without changing the structure), which in turn modulates the enzyme activity. Using this approach, we predicted that the hydride transfer reaction catalyzed by the enzyme dihydrofolate reductase (DHFR) from Escherichia coli in aqueous mixtures of isopropanol (IPA) with water will decrease by ∼3 fold at 20% (v/v) IPA concentration. Stopped-flow kinetic measurements find that the pH-independent khydride rate decreases by 2.2 fold. X-ray crystallographic enzyme structures show no noticeable differences, while computational studies indicate that the transition state and electrostatic effects were identical for water and mixed solvent conditions; quasi-elastic neutron scattering studies show that the dynamical enzyme motions are suppressed. Our approach provides a unique avenue to modulating enzyme activity through changes in enzyme dynamics. Further it provides vital insights that show the altered motions of DHFR cause significant changes in the enzyme's ability to access its functionally relevant conformational substates, explaining the decreased khydride rate. This approach has important implications for obtaining fundamental insights into the role of rate-limiting dynamics in catalysis and as well as for enzyme engineering.

Dynamics of water bound to crystalline cellulose.

Interactions of water with cellulose are of both fundamental and technological importance. Here, we characterize the properties of water associated with cellulose using deuterium labeling, neutron scattering and molecular dynamics simulation. Quasi-elastic neutron scattering provided quantitative details about the dynamical relaxation processes that occur and was supported by structural characterization using small-angle neutron scattering and X-ray diffraction. We can unambiguously detect two populations of water associated with cellulose. The first is "non-freezing bound" water that gradually becomes mobile with increasing temperature and can be related to surface water. The second population is consistent with confined water that abruptly becomes mobile at ~260 K, and can be attributed to water that accumulates in the narrow spaces between the microfibrils. Quantitative analysis of the QENS data showed that, at 250 K, the water diffusion coefficient was 0.85 ± 0.04 × 10-10 m2sec-1 and increased to 1.77 ± 0.09 × 10-10 m2sec-1 at 265 K. MD simulations are in excellent agreement with the experiments and support the interpretation that water associated with cellulose exists in two dynamical populations. Our results provide clarity to previous work investigating the states of bound water and provide a new approach for probing water interactions with lignocellulose materials.

Single-Crystal Time-of-Flight Neutron Diffraction and Magic-Angle-Spinning NMR Spectroscopy Resolve the Structure and 1H and 7Li Dynamics of the Uranyl Peroxide Nanocluster U60.

Single-crystal time-of-flight neutron diffraction has provided atomic resolution of H atoms of H2O molecules and hydroxyl groups, as well as Li cations in the uranyl peroxide nanocluster U60. Solid-state magic-angle-spinning nuclear magnetic resonance (MAS NMR) spectroscopy was used to confirm the dynamics of these constituents, revealing the transportation of Li atoms and H2O through cluster walls. H atoms of hydroxyl units that are located on the cluster surface are involved in the transfer of H2O and Li cations from inside to outside and vice versa. This exchange occurs as a concerted motion and happens rapidly even in the solid state. As a consequence of its large size and open hexagonal pores, U60 exchanges Li cations more rapidly compared to other uranyl nanoclusters.

Solution (31)P NMR Study of the Acid-Catalyzed Formation of a Highly Charged {U24Pp12} Nanocluster, [(UO2)24(O2)24(P2O7)12](48-), and Its Structural Characterization in the Solid State Using Single-Crystal Neutron Diffraction.

The first neutron diffraction study of a single crystal containing uranyl peroxide nanoclusters is reported for pyrophosphate-functionalized Na44K6[(UO2)24(O2)24(P2O7)12][IO3]2·140H2O (1). Relative to earlier X-ray studies, neutron diffraction provides superior information concerning the positions of H atoms and lighter counterions. Hydrogen positions have been assigned and reveal an extensive network of H-bonds; notably, most O atoms present in the anionic cluster accept H-bonds from surrounding H2O molecules, and none of the surface-bound O atoms are protonated. The D4h symmetry of the cage is consistent with the presence of six encapsulated K cations, which appear to stabilize the lower symmetry variant of this cluster. (31)P NMR measurements demonstrate retention of this symmetry in solution, while in situ (31)P NMR studies suggest an acid-catalyzed mechanism for the assembly of 1 across a wide range of pH values.